Dissolving microneedle patches comprising corticosteroid

ABSTRACT

In the preferred embodiment of the present invention, a patch of dissolving microneedles loaded with active ingredients to be applied to skin for treating skin conditions is provided. As seen in FIG.  1,  the dissolving microneedle patch ( 10 ) comprises a substrate ( 12 ) and a plurality of microneedles ( 14 ) which extends from the substrate. The dissolving microneedle patch ( 10 ) is made of a matrix material and at least one active ingredient such as a corticosteroid, namely triamcinolone (TAC). The matrix material is made of bio-compatible materials such as hyaluronic acid (HA), polyvinylpyrrolidone (PVP), or mixture of them, which dissolve rapidly when they are in contact with the inner skin. The active ingredient is loaded onto individual patches with the desirable dosage ranging from 0.01 mg-1.0 mg.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a § 371 national phase application ofPCT/SG2019/050014 filed Jan. 10, 2019 entitled “DISSOLVING MICRONEEDLEPATCHES COMPRISING CORTICOSTEROID,” which claims the benefit of andpriority to Singapore Patent Application No. 10201800072Y filed Jan. 3,2018, the contents of which being incorporated by reference in theirentireties herein.

FIELD OF THE INVENTION

The present invention generally relates to home-based treatments forskin conditions. More particularly, the present invention pertains todrug-laden microneedle patches having tailored shapes for treatingchronic skin conditions such as keloids, etc.

BACKGROUND OF THE INVENTION

Keloid scars are a common skin disorder with significant morbidity.Prominent symptoms include pain and itch which can significantly impactthe quality of life. The undesirable, disfiguring appearance can alsolead to emotional distress and psychosocial burden. Current therapeuticoptions are limited. The first-line option is intra-lesionalcorticosteroid injections which, due to the sensitivity of keloids, ispainful and precludes treatment in many patients. Moreover, there is ahigh recurrence rate of near 50% Other commonly employed therapiesinclude cryotherapy, radiotherapy and occlusive dressings which havepoor efficacy rates, low patient adherence and a high rate ofrecurrence.

At the National Skin Centre (NSC) in Singapore, in 2012, there were 675new cases of keloids seen. Statistics show that keloids account for11.5-34.5 million surgical procedures globally and represent a SGD $7billion market size. Given the incidence of keloids both locally andworldwide and the limitations with current treatment, there is clearlyan unmet need for more effective, tolerable, and reliable therapy.

The current treatment is direct injection of corticosteroid into thekeloids using syringes, which is painful. If the keloids cover a largearea on the skin, multiple injections are performed to spread thecorticosteroid over the entire keloids as uniform as possible. Thisrequires great dexterity and dermatological experience and is normallycarried out by a specialist or medical personnel. The shortcomings ofthe present practice are that the parenteral injection is painful and itis almost impossible to spread the drug evenly across the keloid, evenwith experienced medical personnel.

Over the past decade, microneedle technology has been increasingly triedfor the treatment of skin conditions. The decreased likelihood ofcausing pain, infection, and injury makes microneedles a great platformfor self-administration of drugs. In recent years, drug-loadeddissolving hyaluronic acid microneedles have received extensiveattention in transdermal drug delivery. In contrast to drug-coatedmicroneedles, they do not have the risk of leaving foreign material inthe skin if broken, can encapsulate sensitive biomolecules within theneedle shafts to deliver a specific dosage of drugs, and may have ahigher drug-loading capacity.

In particular, microneedle patches are advantageous in treating keloidsbecause the microneedles can deliver the corticosteroid into the keloidspainlessly and easily without needing the help of trained medicalpersonnel. Moreover, the microneedle patches can be custom-made intoindividual keloids' shapes so that the corticosteroid is delivered toand spread evenly over the keloids' site, without spilling over to thenormal skin, as corticosteroid is harmful to normal skin.

U.S. Pat. No. 9,539,418 B2 awarded to Cosmed Pharmaceutical reported amicroneedle patch made of proteoglycan and U.S. Pat. No. 8,167,152 B2awarded to Cosmed Pharmaceutical reported a microneedle patch made ofhyaluronic acid and collagen. Both patents report dissolvingmicroneedles but they do not contain drug for treating skin conditionssuch as keloids.

PCT Patent Publication No. WO 2015/122838A1 assigned to Lim et. al.reported a rapidly dissolvable microneedle and the fabrication methodthereof, which is reference in its entirety in this present invention.

To our knowledge, there is no published data on the use of drug-embeddeddissolving microneedles in the treatment of keloids. As such, themotivation of the present invention is to provide a home-based solutionwhere a custom-shaped microneedle patch loaded with corticosteroid canbe applied by a patient at home on daily or weekly basis. The presentinvention bring forth a is translates to less pain, improved efficacy,feasibility for self-administration, better patient adherence and alower risk of systemic absorption and local side effects of steroidtherapy.

BRIEF SUMMARY OF THE INVENTION

The current practice in treating chronic skin conditions which requireconstant injection of drugs on the affected skin sites, poses severalproblems as follows:

-   -   (a) the trauma they experience during the intradermal        injections,    -   (b) the inconvenience they endure for every visit to the        hospital for such injections,    -   (c) the uneven delivery of drug across the skin sites (e.g.        keloids) by hands,

Considering these problems, there is a long-felt need for a drugdelivery system to provide certain desirable features such as:

-   -   (a) painlessness,    -   (b) self-administration, and    -   (c) precision in drug delivery in terms of depth and affected        area.

Now embodiments of the present invention will be provided to solve thecurrent problems of chronic skin conditions by providing the desirablesolutions mentioned above.

In an embodiment of the present invention, a patch of dissolvingmicroneedles loaded with active ingredients to be applied to skin fortreating skin conditions is provided. As seen in FIG. 1, the dissolvingmicroneedle patch 10 comprises a substrate 12 and a plurality ofmicroneedles 14 which extends from the substrate. The dissolvingmicroneedle patch 10 is made of a matrix material and at least oneactive ingredient such as a corticosteroid, namely triamcinolone (TAC).The matrix material is made of bio-compatible materials such ashyaluronic acid (HA), polyvinylpyrrolidone (PVP), or mixture of them,which dissolve rapidly when they are in contact with the inner skin. Theactive ingredient is loaded onto individual patches with the desirabledosage ranging from 0.01 mg-1.0 mg.

The dissolving microneedle patch 10 may be accompanied by a skinprotection coating 20 which has a hole tailored to the target keloid'sshape so that the active ingredient can be effectively delivered intothe keloid while the excess will be masked out by the skin protectioncoating 20. The skin protection coating 20 is made of inert materialincluding but not limited to woven or non-woven fabrics, wax, polymerfilms, etc. and is adhered on the targeted skin site to only expose thekeloid to the dissolving microneedle patch 10.

For delivering the active ingredients loaded in the microneedles, thedissolving microneedle patch 10 is applied on the affected skin site(such as a keloid) and is held on with mild pressure for a length oftime, e.g. from 10 seconds to 10 minutes.

The application of the dissolving microneedle patch can be carried inseveral modes, including using a spring applicator and a handle.

Another embodiment of the present invention includes the dissolvingmicroneedle patch 30 being affixed on a skin adhesive 32. The skinprotection coating 40 is an external separate piece that is applied onthe skin beforehand to expose only the keloid to the dissolvingmicroneedle patch 30. This adhesive dissolving microneedle patch 30 isapplied on the skin with fingers and it is adhered on the skin for alength of time. The patient may use his fingers to exert mild pressureon the patch from time to time.

BRIEF DESCRIPTION OF THE DRAWINGS

Many aspects of the present disclosure can be better understood withreference to the following drawings. The components in the drawings arenot necessarily to scale, with emphasis instead being placed uponclearly illustrating the principles of the disclosure. Moreover, in thedrawings, like reference numerals designate corresponding partsthroughout the several views.

FIG. 1 shows a dissolving microneedle patch 10 comprising a substrate 12from which a plurality of microneedles 14 extends.

FIG. 2 shows an external skin protection coating 20 having a throughhole for only exposing a targeted skin site such as a keloid. Thecoating 20 comprises a bottom surface 22 having an adhesive coating foraffixing onto the skin, a top surface 24 for receiving the microneedles,and a hole 26 to expose a keloid while masking out the normal skin.

FIG. 3 shows a dissolving microneedle patch 30 and a microneedletemplate 32 having a cavity 34 and a plurality of microneedle cavities36.

FIG. 4 shows a spring applicator 40 which can be used to apply thedissolving microneedle patch on the skin, comprising a transparentcompressor cap 42 and a trigger button 44.

FIG. 5 shows schematically the application of a dissolving microneedlepatch 50 onto a skin site such as a keloid 52 which is masked out by askin protection coating 54.

FIG. 6 shows a keloid treated with the dissolving microneedles versus acontrol keloid on the same patient—at baseline, 4 weeks after treatment,and after another 4 weeks of withheld treatment.

DETAILED DESCRIPTION

It is the objective of the present invention to provide a drug deliverysolution for the current intradermal injection practice for treatingchronic skin conditions such as keloid scars. Currently, patients withkeloid scars have to visit dermatologist regularly for the intradermalinjections of corticosteroid such as triamcinolone (TAC). As mentionedearlier, a dissolving microneedle patch laded with TAC provides ahome-based alternative for the patients because this patch is painlessand easy to use. The present invention aims to cater to the uniformdelivery of active ingredients across a targeted skin site, includingbut not limited to a keloid, by plurality of dissolving microneedles.FIG. 1 shows an example of such a drug-laden dissolving microneedlepatch 10. As shown in the figure, the patch comprises a substrate 12from which a plurality of dissolving microneedles 14 extend. Themicroneedles are typically 100 um to 1,000 um tall, with thepeak-to-peak distance of 500 um to 3,000 um. For example, a 10×10 arrayof microneedle patch with a 500 um peak-to-peak distance will haveroughly a 5 mm×5 mm=25 mm² in area. Due to manufacturing convenience,the dissolving microneedle patch 10 normally has rectangular shapes insizes, typically ranging from 5 mm×5 mm to 100 mm×100 mm. The activeingredient is loaded onto individual patches with the desirable dosageranging from 0.001 mg-1.0 mg per mm², or more particularly 0.001 mg-0.01mg per mm².

Quite often the targeted skin sites have irregular shapes. By applyingthe rectangular shaped dissolving microneedle patches, the surroundingnormally skin will also be injected with the active ingredients, whichis not desirable because the normal tissues will be damaged. In order toprevent this undesirable event from happening, the present inventionprovides a skin protection coating which basically covers thesurrounding normal skin with inert material and prevents the dissolvingmicroneedles from penetrating it. FIG. 2 shows an external skinprotection coating 20, which comprises a bottom surface 22 coated withskin adhesive, a top surface 24 for receiving the microneedles, and ahole 26 made to expose a keloid. The external skin protection coating 20is a thin layer of inert material such as woven or non-woven fabric,wax, polymer films, etc. that adheres to the skin before the dissolvingmicroneedles are applied to the skin. The external skin protectioncoating 20 can take the form of a film that can be worn on a keloid, orit can take the form of a liquid like wax, which takes a liquid formwhen it is applied on the skin with a brush but rapidly solidifies intoa solid layer which firmly adhere to the skin to mask out the normalskin and protect it from delivery of TAC by the microneedles.

The fabrication of the dissolving microneedle patch is reported inpatent document WO 2015/122838A1, which is incorporated by reference inits entirety herein. FIG. 3 shows the process flow of making adissolving microneedle patch 30 on a microneedle template 32. Themicroneedle template 32 comprises a cavity 34 and a plurality ofmicroneedle cavities 36. The dissolving microneedle patch 30 is made ofa matrix material and at least one active ingredient such as acorticosteroid, namely triamcinolone (TAC). The matrix material is madeof bio-compatible materials such as hyaluronic acid (HA),polyvinylpyrrolidone (PVP), or mixture of them, which dissolve rapidlywhen they are in contact with the inner skin. The active ingredienttriamcinolone acetonide TAC is only mildly soluble in water.

Fabrication of Dissolving Microneedle Patch. In one example, the activeingredient TAC is pre-mixed with the matrix material and the mixture iscast onto the microneedle template 32 (FIG. 3) to form the dissolvingmicroneedle patch. The microneedle template has a cavity 34 withdimensions of 8 mm×8 mm×1 mm (height), or 64 ul in volume, which furthercomprises a plurality of microneedle cavities 36. The matrix material isHA 0.6 g/ml and the active ingredient is TAC 10 mg/ml. The mixing ratiois HA:TAC=5:1. 64 ul of the mixture is loaded into the cavity 34 and themicroneedle template 32 is subjected to a centrifugal force at3,000-5,000 RPM for 1-2 minutes. The centrifugal force will push themixture comprising TAC into the microneedle cavities 36. Since TAC isnot soluble in water, a considerable amount of TAC in the cavity 34 isforced to fill the microneedle cavities 36.

Alternatively, the active ingredient and the matrix material can beloaded individually into the cavity 34 of the microneedle template 32.The matrix material may be 50 ul of HA at 0.6 g/ml and the activeingredient may be 10 ul of TAC at 10 mg/ml, which makes up 0.1 mg perpatch. The loaded microneedle template 32 is then subjected to acentrifugal force of 3,000 RPM to 5,000 RPM for 1-2 minutes to fill upthe microneedle cavities 36. Due to the fact that TAC is insoluble, thecentrifuging step distributes TAC across the microneedle cavities 36evenly and pushes TAC into the microneedle cavities 36. Subsequently,the filled microneedle template will be left in a controlled environmentso that the microneedle patch solidifies. The solidification duration inroom temperature typical ranges from 4-16 hours. Finally, the solidifieddissolving microneedle patch 30 is de-molded from the microneedletemplate 32.

Application of Dissolving Microneedle Patches on the Skin. Theapplication of dissolving microneedle patches on the skin can beachieved by several methods. FIG. 4 shows a spring applicator 40 whichis used for applying a dissolving microneedle patch on the skin. Thespring applicator 40 comprises a transparent compressor cap 42 forfixing and tensioning the skin site prior to application and a triggerbutton 44 is pushed to release the spring for applying the dissolvingmicroneedle patch 46 onto the skin at high speed. The penetration speedof the spring applicator 40 is roughly 2 m/s and the impact force is1.0-1.6N. The use of spring applicator warrants consistency andrepeatability of the application of dissolving microneedle patches.

In the case where the targeted skin site is a large area, the springapplicator is not able to apply large patches. Therefore, large patchescan only be applied by hands. However, as mentioned earlier, largepatches may overreach the normal skin area and deliver corticosteroid tothe normal skin site, which is undesirable. FIG. 5 shows a schematicprocess flow of how a dissolving microneedle patch 50 and an externalskin protection coating 52 are applied to target only the affected skinsites such as keloids 54. The external skin protection coating 52 masksout the normal skin and only exposes the keloid to receive themicroneedles. The external skin protection coating 52 can take the formof a skin adhesive, which has one surface having skin adhesive foraffixation on the skin and another open surface for receivingmicroneedles. Alternatively, the external skin protection coating 52 cantake the form of a wax, which can be in liquid form and is applied ontothe skin with a brush, and rapidly solidifies to form a rigid layer onthe skin to receive microneedles.

Clinical Trial. The dissolving microneedle patches were made and loadedwith 0.1 mg of TAC and were applied with the spring applicator. Thetrial was carried out at National Skin Centre in Singapore. This was asingle-blinded, intra-individual randomized controlled clinical trialwhere two keloids on each subject were randomized to the followingtreatment groups:

-   -   1. Control group: No treatment    -   2. Dissolving microneedles group: Triamcinolone-embedded,        dissolving hyaluronic acid microneedles

At baseline, volume measurements and patient assessments of pain anditch were recorded. Subjects were treated with the dissolvablemicroneedles over 4 weeks and measurements were repeated. A final visitwas scheduled at 4 weeks post-treatment and measurements taken again(Table 1).

TABLE 1 Study Schedule Visits Action taken Baseline (Week 0) Patientassessment and randomization Measurements 1^(st) Visit (Week 4) Review -conclusion of treatment Measurements 2^(nd) Visit (Week 8) Review andmeasurements

A total of 17 patients, comprising of 15 (88.2%) males and 2 (11.8%)females were enrolled into the study. A majority of the patients wereChinese (n=12, 70.6%), Malay (n=4, 23.5%), and others (n=1, 5.9%). All17 patients completed the study.

After applying the treatment for 4 weeks, significant reduction in meankeloid size was seen in the Dissolving microneedles group from 171.6 mm3in Visit 1 to 149.6 mm³ in Visit 2 (p-value 0.001, Table 2, FIG. 6). Thereduction in the Dissolving microneedles group (mean change: −22.1±28.0)was greater than the Control group (mean change: 6.7±58.3,p-value=0.034). In the subsequent 4 weeks, when no treatment was givenfrom Visit 2 to Visit 3, it was observed that the keloids treated in theDissolving microneedles group (p-value=0.005) grew back in size.

TABLE 2 Keloid size/volume by Visit and Intervention Change from Changefrom Change from Visit 1 Visit 2 Visit 3 Visit 1 to 2 Visit 2 to 3 Visit1 to 3 (n = 17) (n = 17) (n = 17) (n = 17) (n = 17) (n = 17) Keloid Size(mm³) Control group Mean ± SD 182.0 ± 330.1 188.6 ± 376.1 186.8 ± 368.4 6.7 ± 58.3 −1.9 ± 11.7 4.8 ± 55.1 Median (min, max) 66.3 (7.0, 1341.2)58.2 (5.4, 1563.2) 57.0 (7.5, 1537.5) −1.0 (−67.7, 222.0) 1.3 (−27.9,14.1) 0.5 (−95.5, 196.3) p-value for — — — 0.545 0.498 0.663 comparingeach visit and subsequent visit for intervention = Control Dissolvingmicroneedle group Mean ± SD 171.6 ± 432.6 149.6 ± 418.2 172.3 ± 448.8−22.1 ± 28.0 22.8 ± 38.5 0.7 ± 25.1 Median (min, max) 35.7 (8.4, 1826.9)28.2 (3.0, 1761.2) 38.8 (7.2, 1892.3) −7.2 (−75.7, 19.8)   5.9 (−1.9,131.2) 0.6 (−50.2, 65.4)  p-value for — — — 0.001 0.005 0.917 comparingeach visit and subsequent visit for intervention = Dissolving p-valuefor — — — 0.034 0.001 0.765 comparing each visit and subsequent visitbetween Dissolving and Control Note: Keloid Size (mm³) was based on themean of 3 measurements.

Subjects from the Dissolving microneedles group experiencedsignificantly lesser itch after 4 weeks of treatment (Table 3) from1.7±2.3 at Visit 1 to 1.0±1.9 at Visit 2 (p-value=0.005) and the itchreduction (mean change: −0.7±1.1) was more significant than the Controlgroup (mean change: 0.4±2.0, p-value=0.005).

TABLE 3 Itch score on a 1-10 numerical scale by Visit and InterventionChange from Change from Change from Visit 1 Visit 2 Visit 3 Visit 1 to 2Visit 2 to 3 Visit 1 to 3 (n = 17) (n = 17) (n = 17) (n = 17) (n = 17)(n = 17) Itch score Control group Mean ± SD 1.8 ± 2.3 2.2 ± 2.7 1.4 ±2.2 0.4 ± 2.0 −0.8 ± 1.6 −0.4 ± 1.8 Median (min, max) 0.0 (0.0, 7.0) 1.0(0.0, 8.0) 0.0 (0.0, 7.0) 0.0 (−2.0, 8.0) 0.0 (−4.0, 2.0) 0.0 (−3.5,4.0) p-value for — — — 0.329 0.036 0.402 comparing each visit andsubsequent visit for intervention = Control Dissolving microneedle groupMean ± SD 1.7 ± 2.3 1.0 ± 1.9 0.9 ± 1.9 −0.7 ± 1.1 −0.1 ± 0.6 −0.8 ± 1.3Median (min, max) 0.0 (0.0, 7.5) 0.0 (0.0, 7.5) 0.0 (0.0, 7.5) 0.0(−3.5, 1.0) 0.0 (−1.0, 1.5) 0.0 (−3.5, 1.5) p-value for — — — 0.0050.507 0.002 comparing each visit and subsequent visit for intervention =Dissolving p-value for — — — 0.005 0.046 0.272 comparing each visit andsubsequent visit between Dissolving and Control

1. A dissolving microneedle patch, comprising: a matrix material and anactive pharmaceutical ingredient, wherein the active pharmaceuticalingredient is a corticosteroid.
 2. The dissolving microneedle patch ofclaim 1, wherein the matrix material comprises hyaluronic acid.
 3. Thedissolving microneedle patch of claim 1, wherein the matrix materialcomprises polyvinylpyrrolidone.
 4. The dissolving microneedle patch ofclaim 1, wherein the corticosteroid is triamcinolone acetonide.
 5. Thedissolving microneedle patch of claim 1, wherein the corticosteroid doseranges from 0.01 mg to 1.0 mg per patch.
 6. The dissolving microneedlepatch of claim 1, further comprising an external skin protection coatingfor protecting normal skin from receiving the microneedles.
 7. Thedissolving microneedle patch of claim 6, wherein the external skinprotection coating further comprises a first surface to be adhered toskin and a second surface for receiving the microneedles.
 8. Thedissolving microneedle patch of claim 6, wherein the external skinprotection coating comprises a solidified form of a liquid wax appliedon skin that forms a protective layer.
 9. The dissolving microneedlepatch of claim 6, wherein the external skin protection coating is madeof a skin adhesive having a first surface coated with skin adhesive anda second surface to receive the microneedles.
 10. A method offabricating a dissolving microneedle patch, comprising: providing amicroneedle template, the microneedle template comprising a cavity and aplurality of microneedle cavities; loading a matrix material and anactive pharmaceutical ingredient into the cavity of the microneedletemplate, wherein the active pharmaceutical ingredient is acorticosteroid; subjecting the microneedle template as loaded to acentrifuging force so that the matrix material and the corticosteroidfill up the microneedle cavities; drying the microneedle template asfilled.
 11. The method of fabricating the dissolving microneedle patchof claim 10, wherein the loading of the matrix material and the activepharmaceutical ingredient are performed separately.
 12. The method offabricating the dissolving microneedle patch of claim 10, wherein thematrix material comprises sodium hyaluronate, polyvinylpyrrolidone, or amixture of both.
 13. The method of fabricating the dissolvingmicroneedle patch of claim 10, wherein the corticosteroid istriamcinolone acetonide.
 14. The method of fabricating the dissolvingmicroneedle patch of claim 12, wherein the concentration of sodiumhyaluronate is 0.2-1.0 g/ml.
 15. The method of fabricating thedissolving microneedle patch of claim 13, wherein the concentration oftriamcinolone acetonide is 10-40 mg/ml.